Diabetic nephropathy is a major cause of end-stage renal disease in humans. Early in the course of insulin-dependent diabetes mellitus, the glomerular filtration rate may be increased above normal. This glomerular hyperfiltration (GH) is, at least in part, responsible for the development of diabetic nephropathy. The purpose of this proposal is to identify the factor(s) responsible for this state of GH using the diabetic dog as the experimental model. In in-vivo studies in the conscious, trained dog, we will identify the role which hyperglycemia, insulin deficiency, pancreatic glucagon, atrial natriuretic peptide, vasodilatory prostaglandins, norepinephrine and angiotensin 11 play in the GH. As any effect of these factors on GH is likely expressed in the individual glomerular units, we will identify the effect of these factors on the function of isolated renal afferent and efferent arterioles as well as intact glomerular units studied in-vitro Identification of the factor(s) responsible for GH will potentially lead to further studies which will elucidate the cellular mechanism(s) by which the factors are expressed. Further, the results of these studies should lead to the development of therapeutic regimens aimed at preventing or ameliorating diabetic nephropathy.